Studies On The Total Synthesis Of Antitumor Marine Alkaloid ET-743

ET-743(Ecteinascidin 743)was isolated from the Caribbean tunicate Ecteinascidia turbinata by Rinehart and co-workers in 1986.Because of its remarkable antitumor activity,this molecule was approved by FDA and used clinically as a drug(Trabectedin/Yondelis).Structurally,ET-743 belongs to the tetrahydroisoquinoline alkaloids,possesses an aza-bicyclo[3.3.1] system and a 10-member sulfur-containing bridge ring,highlighting its unprecedented and synthetically challenging molecular scaffold.The potent biological activity and structural characteristic and complexity renders ET-743 an attractive target for total synthesis both in academia and industry.In this paper,we tried to explore the synthesis of ET-743 from easily available material N,N’-diacetylglycine anhydride.This dissertation is divided into the following two parts:1.A brief introduction of previous total synthesis of ET-743,focusing on the construction of its unique aza-bicyclo[3.3.1] system(B.C.D rings)and the 10-member sulfur-containing bridge ring(F ring).As for the former,the synthetic strategy includes Pictet-Spengler and Mannich cyclization by Corey’s group,Aldol,Ugi and Heck reaction by Fukuyama’s group,Aldol,Strecker and Pictet-Spengler reaction by Zhu’s group,etc;As for the latter,the synthetic strategy includes sulf-Michael addition in Corey’s synthesis,sulf-nucleophilic substitution in Fukuyama’s synthesis,etc.2.Based on the Perkin/nucleophilic substitutuion/Perkin cascade reaction designed by our group,the synthetic route of ET-743 was investigated.This section also involves optimization of substrates’ synthesis route,regulation of regioselectivity for subsequent Friedel-Crafts reaction,etc.